ES2313328T3 - Procedimiento para la preparacion de 42-esteres de rapamicina y 32-esteres de fk-506 con acido dicarboxilico, precursores para conjugados de rapamicina y anticuerpos. - Google Patents

Procedimiento para la preparacion de 42-esteres de rapamicina y 32-esteres de fk-506 con acido dicarboxilico, precursores para conjugados de rapamicina y anticuerpos. Download PDF

Info

Publication number: ES2313328T3
Authority: ES; Spain
Prior art keywords: lipase; rapamycin; procedure; reaction; dicarboxylic
Prior art date: 2004-04-14
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired - Lifetime

Application number

ES05735488T

Other languages

English (en)

Spanish (es)

Inventor

Jianxin Gu

Ping Cai

Mark E. Ruppen

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Wyeth LLC

Original Assignee

Wyeth LLC

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2004-04-14

Filing date

2005-04-12

Publication date

2009-03-01

2005-04-12 Application filed by Wyeth LLC filed Critical Wyeth LLC

2009-03-01 Application granted granted Critical

2009-03-01 Publication of ES2313328T3 publication Critical patent/ES2313328T3/es

2025-04-12 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Links

QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 title claims abstract description 102
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ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 title claims abstract description 93
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TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
239000001384 succinic acid Substances 0.000 description 1
IIACRCGMVDHOTQ-UHFFFAOYSA-N sulfamic acid Chemical class NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
201000000596 systemic lupus erythematosus Diseases 0.000 description 1
125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
230000004614 tumor growth Effects 0.000 description 1
208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 1
208000019553 vascular disease Diseases 0.000 description 1
239000002351 wastewater Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/188—Heterocyclic compound containing in the condensed system at least one hetero ring having nitrogen atoms and oxygen atoms as the only ring heteroatoms

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Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Wood Science & Technology (AREA)
Life Sciences & Earth Sciences (AREA)
Engineering & Computer Science (AREA)
Zoology (AREA)
Biotechnology (AREA)
Microbiology (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Health & Medical Sciences (AREA)
Biochemistry (AREA)
Bioinformatics & Cheminformatics (AREA)
General Engineering & Computer Science (AREA)
General Health & Medical Sciences (AREA)
Genetics & Genomics (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Preparation Of Compounds By Using Micro-Organisms (AREA)
Peptides Or Proteins (AREA)

ES05735488T 2004-04-14 2005-04-12 Procedimiento para la preparacion de 42-esteres de rapamicina y 32-esteres de fk-506 con acido dicarboxilico, precursores para conjugados de rapamicina y anticuerpos. Expired - Lifetime ES2313328T3 (es)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US56196604P	2004-04-14	2004-04-14
US561966P		2004-04-14

Publications (1)

Publication Number	Publication Date
ES2313328T3 true ES2313328T3 (es)	2009-03-01

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ID=34965703

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
ES05735488T Expired - Lifetime ES2313328T3 (es)	2004-04-14	2005-04-12	Procedimiento para la preparacion de 42-esteres de rapamicina y 32-esteres de fk-506 con acido dicarboxilico, precursores para conjugados de rapamicina y anticuerpos.

Country Status (14)

Country	Link
US (2)	US7445916B2 (pl)
EP (1)	EP1735321B1 (pl)
JP (1)	JP2007532655A (pl)
CN (1)	CN1942478A (pl)
AT (1)	ATE410431T1 (pl)
AU (1)	AU2005238432A1 (pl)
BR (1)	BRPI0509810A (pl)
CA (1)	CA2562962A1 (pl)
DE (1)	DE602005010228D1 (pl)
DK (1)	DK1735321T3 (pl)
ES (1)	ES2313328T3 (pl)
MX (1)	MXPA06011882A (pl)
PL (1)	PL1735321T3 (pl)
WO (1)	WO2005105812A1 (pl)

Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
NZ537829A (en) *	2002-07-30	2006-09-29	Wyeth Corp	Parenteral formulations containing a rapamycin hydroxyester
AU2005238432A1 (en) *	2004-04-14	2005-11-10	Wyeth	Process for preparing rapamycin 42-esters and FK-506 32-esters with dicarboxylic acid, precursors for rapamycin conjugates and antibodies
CA2562164A1 (en) *	2004-04-27	2005-11-10	Wyeth	Labeling of rapamycin using rapamycin-specific methylases
MX2007001676A (es) *	2004-08-10	2007-04-12	Wyeth Corp	Derivados de 42-ester de rapamicina con acido 2,2-bis(hidroximetil)propionico y metodos para hacer los mismos.
AR058282A1 (es) *	2005-12-07	2008-01-30	Wyeth Corp	Forma cristalina purificada de cci-779, un proceso para la preparacion del mismo, un metodo para monitorear la cristalizacion del cci-779, un kit y una composicion farmaceutica que lo comprenden y su uso en la fabricacion de un medicamento para el tratamiento del cancer.
US7622578B2 (en) *	2005-12-07	2009-11-24	Wyeth	Scalable process for the preparation of a rapamycin 42-ester from a rapamycin 42-ester boronate
BRPI0619592A2 (pt) *	2005-12-07	2016-09-06	Wyeth Corp	métodos para medir a qualidade da partícula de um composto de rapamicina, para determinar o tamanho de partícula médio de uma amostra e a cristalinidade de um composto de rapamicina, e para a purificação de rapamicina
MX2008011458A (es) *	2006-03-07	2008-09-24	Wyeth Corp	Procedimiento para preparar conjugados de polietilenglicol solubles en agua de inmunosupresores de macrolidos.
US8022188B2 (en) *	2006-04-24	2011-09-20	Abbott Laboratories	Immunosuppressant binding antibodies and methods of obtaining and using same
US8414525B2 (en)	2006-11-20	2013-04-09	Lutonix, Inc.	Drug releasing coatings for medical devices
US8414909B2 (en)	2006-11-20	2013-04-09	Lutonix, Inc.	Drug releasing coatings for medical devices
US8414526B2 (en)	2006-11-20	2013-04-09	Lutonix, Inc.	Medical device rapid drug releasing coatings comprising oils, fatty acids, and/or lipids
US9700704B2 (en)	2006-11-20	2017-07-11	Lutonix, Inc.	Drug releasing coatings for balloon catheters
US8998846B2 (en)	2006-11-20	2015-04-07	Lutonix, Inc.	Drug releasing coatings for balloon catheters
US8425459B2 (en)	2006-11-20	2013-04-23	Lutonix, Inc.	Medical device rapid drug releasing coatings comprising a therapeutic agent and a contrast agent
US8414910B2 (en)	2006-11-20	2013-04-09	Lutonix, Inc.	Drug releasing coatings for medical devices
US20080276935A1 (en)	2006-11-20	2008-11-13	Lixiao Wang	Treatment of asthma and chronic obstructive pulmonary disease with anti-proliferate and anti-inflammatory drugs
US9737640B2 (en)	2006-11-20	2017-08-22	Lutonix, Inc.	Drug releasing coatings for medical devices
US8430055B2 (en)	2008-08-29	2013-04-30	Lutonix, Inc.	Methods and apparatuses for coating balloon catheters
TW200845960A (en) *	2007-04-05	2008-12-01	Wyeth Corp	Wortmannin-rapalog conjugate and uses thereof
EP2365802B1 (en)	2008-11-11	2017-08-02	The Board of Regents,The University of Texas System	Microcapsules of rapamycin and use for treating cancer
US9283211B1 (en)	2009-11-11	2016-03-15	Rapamycin Holdings, Llc	Oral rapamycin preparation and use for stomatitis
SI2885007T1 (sl)	2012-08-16	2018-12-31	Pfizer Inc.	Postopki in kompozicije glikokonjugacij
EP2968281B1 (en)	2013-03-13	2020-08-05	The Board of Regents of The University of Texas System	Mtor inhibitors for prevention of intestinal polyp growth
US9700544B2 (en)	2013-12-31	2017-07-11	Neal K Vail	Oral rapamycin nanoparticle preparations
AU2014373683B2 (en)	2013-12-31	2020-05-07	Rapamycin Holdings, Llc	Oral rapamycin nanoparticle preparations and use
EP3848065B1 (en)	2017-05-15	2023-07-26	C. R. Bard, Inc.	Medical device with drug-eluting coating and intermediate layer
EP3880266B1 (en)	2018-11-14	2025-05-07	Lutonix, Inc.	Medical device with drug-eluting coating on modified device surface
WO2020209828A1 (en)	2019-04-08	2020-10-15	Bard Peripheral Vascular, Inc.	Medical device with drug-eluting coating on modified device surface
CN118027062B (zh) *	2023-11-03	2025-02-14	沈阳药科大学	一种雷帕霉素前药及其纳米制剂的制备和应用

Family Cites Families (59)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
ZA737247B (en)	1972-09-29	1975-04-30	Ayerst Mckenna & Harrison	Rapamycin and process of preparation
US4316885A (en) *	1980-08-25	1982-02-23	Ayerst, Mckenna And Harrison, Inc.	Acyl derivatives of rapamycin
US4650803A (en) *	1985-12-06	1987-03-17	University Of Kansas	Prodrugs of rapamycin
US5210030A (en)	1990-06-25	1993-05-11	Merck & Co., Inc.	Process for selectively acylating immunomycin
US5023264A (en) *	1990-07-16	1991-06-11	American Home Products Corporation	Rapamycin oximes
US5378696A (en) *	1990-09-19	1995-01-03	American Home Products Corporation	Rapamycin esters
US5221670A (en) *	1990-09-19	1993-06-22	American Home Products Corporation	Rapamycin esters
PT98990A (pt)	1990-09-19	1992-08-31	American Home Prod	Processo para a preparacao de esteres de acidos carboxilicos de rapamicina
US5130307A (en) *	1990-09-28	1992-07-14	American Home Products Corporation	Aminoesters of rapamycin
US5233036A (en) *	1990-10-16	1993-08-03	American Home Products Corporation	Rapamycin alkoxyesters
US5078999A (en)	1991-02-22	1992-01-07	American Home Products Corporation	Method of treating systemic lupus erythematosus
US5080899A (en)	1991-02-22	1992-01-14	American Home Products Corporation	Method of treating pulmonary inflammation
US5120842A (en)	1991-04-01	1992-06-09	American Home Products Corporation	Silyl ethers of rapamycin
US5100883A (en)	1991-04-08	1992-03-31	American Home Products Corporation	Fluorinated esters of rapamycin
US5118678A (en) *	1991-04-17	1992-06-02	American Home Products Corporation	Carbamates of rapamycin
US5118667A (en)	1991-05-03	1992-06-02	Celtrix Pharmaceuticals, Inc.	Bone growth factors and inhibitors of bone resorption for promoting bone formation
US5130507A (en) *	1991-05-23	1992-07-14	Eaton Corporation	Capacitive switch assembly
ATE135583T1 (de)	1991-06-18	1996-04-15	American Home Prod	Verwendung von rapamycin zur behandlung von t- zellen lymphom/leukämie bei erwachsenen
US5162333A (en) *	1991-09-11	1992-11-10	American Home Products Corporation	Aminodiesters of rapamycin
US5177203A (en) *	1992-03-05	1993-01-05	American Home Products Corporation	Rapamycin 42-sulfonates and 42-(N-carboalkoxy) sulfamates useful as immunosuppressive agents
US5256790A (en) *	1992-08-13	1993-10-26	American Home Products Corporation	27-hydroxyrapamycin and derivatives thereof
GB9221220D0 (en) *	1992-10-09	1992-11-25	Sandoz Ag	Organic componds
US5489680A (en) *	1992-10-13	1996-02-06	American Home Products Corporation	Carbamates of rapamycin
US5434260A (en) *	1992-10-13	1995-07-18	American Home Products Corporation	Carbamates of rapamycin
US5480988A (en) *	1992-10-13	1996-01-02	American Home Products Corporation	Carbamates of rapamycin
US5480989A (en) *	1992-10-13	1996-01-02	American Home Products Corporation	Carbamates of rapamycin
US5411967A (en) *	1992-10-13	1995-05-02	American Home Products Corporation	Carbamates of rapamycin
US5302584A (en) *	1992-10-13	1994-04-12	American Home Products Corporation	Carbamates of rapamycin
US5262423A (en) *	1992-10-29	1993-11-16	American Home Products Corporation	Rapamycin arylcarbonyl and alkoxycarbonyl carbamates as immunosuppressive and antifungal agents
US5258389A (en) *	1992-11-09	1993-11-02	Merck & Co., Inc.	O-aryl, O-alkyl, O-alkenyl and O-alkynylrapamycin derivatives
US5260300A (en) *	1992-11-19	1993-11-09	American Home Products Corporation	Rapamycin carbonate esters as immuno-suppressant agents
US5252579A (en) *	1993-02-16	1993-10-12	American Home Products Corporation	Macrocyclic immunomodulators
GB9307491D0 (en) *	1993-04-08	1993-06-02	Sandoz Ltd	Organic compounds
WO1994025072A1 (en)	1993-04-23	1994-11-10	American Home Products Corporation	Rapamycin conjugates and antibodies
US5504091A (en) *	1993-04-23	1996-04-02	American Home Products Corporation	Biotin esters of rapamycin
DE69435044T2 (de)	1993-04-23	2008-09-18	Wyeth	Rapamycin - Konjugate und Antikörper
GB2281294A (en)	1993-08-23	1995-03-01	Fujisawa Pharmaceutical Co	Process for producing half esters of the macrolide FK506
US5391730A (en) *	1993-10-08	1995-02-21	American Home Products Corporation	Phosphorylcarbamates of rapamycin and oxime derivatives thereof
US5378836A (en) *	1993-10-08	1995-01-03	American Home Products Corporation	Rapamycin oximes and hydrazones
US5373014A (en) *	1993-10-08	1994-12-13	American Home Products Corporation	Rapamycin oximes
US5385909A (en) *	1993-11-22	1995-01-31	American Home Products Corporation	Heterocyclic esters of rapamycin
US5385908A (en) *	1993-11-22	1995-01-31	American Home Products Corporation	Hindered esters of rapamycin
US5385910A (en) *	1993-11-22	1995-01-31	American Home Products Corporation	Gem-distributed esters of rapamycin
US5389639A (en) *	1993-12-29	1995-02-14	American Home Products Company	Amino alkanoic esters of rapamycin
US5362718A (en)	1994-04-18	1994-11-08	American Home Products Corporation	Rapamycin hydroxyesters
US5463048A (en) *	1994-06-14	1995-10-31	American Home Products Corporation	Rapamycin amidino carbamates
US5491231A (en) *	1994-11-28	1996-02-13	American Home Products Corporation	Hindered N-oxide esters of rapamycin
US5563145A (en) *	1994-12-07	1996-10-08	American Home Products Corporation	Rapamycin 42-oximes and hydroxylamines
US6261813B1 (en) *	1995-09-11	2001-07-17	Albany Molecular Research, Inc.	Two step enzymatic acylation
US5780462A (en) *	1995-12-27	1998-07-14	American Home Products Corporation	Water soluble rapamycin esters
JP2001518784A (ja)	1997-04-09	2001-10-16	アイソテクニカ，インコーポレイテッド	ラパマイシンの特異的部位に対する抗体の産生方法
US6277983B1 (en)	2000-09-27	2001-08-21	American Home Products Corporation	Regioselective synthesis of rapamycin derivatives
US7153983B2 (en) *	2002-03-25	2006-12-26	Council Of Scientific And Industrial Research	Chemo-enzymatic process for the preparation of opticaly enriched β-benzyl-γ-butyrolactones
US6745478B2 (en)	2002-07-18	2004-06-08	Delillo Dominick D.	Multi-purpose work knife
KR20060057605A (ko)	2003-08-07	2006-05-26	와이어쓰	Ｃｃｉ-779의 위치선택적 합성 방법
AU2005233612A1 (en)	2004-04-14	2005-10-27	Wyeth	Proline CCI-779 (proline-rapamycin 42-ester with 2,2-bis (hydroxymethyl) propionic acid) and two-step enzymatic synthesis of proline CCI-779 and CCI-779 using microbial lipase
AU2005238432A1 (en)	2004-04-14	2005-11-10	Wyeth	Process for preparing rapamycin 42-esters and FK-506 32-esters with dicarboxylic acid, precursors for rapamycin conjugates and antibodies
JP4224115B2 (ja) *	2004-04-14	2009-02-12	ワイス	ラパマイシン４２−エステル誘導体の位置特異的合成
EP1781303A4 (en) *	2004-06-30	2008-07-02	Combinatorx Inc	METHOD AND REAGENTS FOR THE TREATMENT OF METABOLISM DISEASES

2005
- 2005-04-12 AU AU2005238432A patent/AU2005238432A1/en not_active Withdrawn
- 2005-04-12 DE DE602005010228T patent/DE602005010228D1/de not_active Expired - Fee Related
- 2005-04-12 WO PCT/US2005/012268 patent/WO2005105812A1/en not_active Ceased
- 2005-04-12 PL PL05735488T patent/PL1735321T3/pl unknown
- 2005-04-12 ES ES05735488T patent/ES2313328T3/es not_active Expired - Lifetime
- 2005-04-12 CA CA002562962A patent/CA2562962A1/en not_active Abandoned
- 2005-04-12 EP EP05735488A patent/EP1735321B1/en not_active Expired - Lifetime
- 2005-04-12 MX MXPA06011882A patent/MXPA06011882A/es active IP Right Grant
- 2005-04-12 CN CNA200580011299XA patent/CN1942478A/zh not_active Withdrawn
- 2005-04-12 US US11/104,349 patent/US7445916B2/en not_active Expired - Lifetime
- 2005-04-12 JP JP2007508443A patent/JP2007532655A/ja not_active Withdrawn
- 2005-04-12 AT AT05735488T patent/ATE410431T1/de not_active IP Right Cessation
- 2005-04-12 DK DK05735488T patent/DK1735321T3/da active
- 2005-04-12 BR BRPI0509810-6A patent/BRPI0509810A/pt not_active IP Right Cessation
2008
- 2008-09-29 US US12/240,230 patent/US7625726B2/en not_active Expired - Fee Related

Also Published As

Publication number	Publication date
WO2005105812A1 (en)	2005-11-10
US20050234087A1 (en)	2005-10-20
ATE410431T1 (de)	2008-10-15
CN1942478A (zh)	2007-04-04
US7625726B2 (en)	2009-12-01
PL1735321T3 (pl)	2009-04-30
BRPI0509810A (pt)	2007-09-18
CA2562962A1 (en)	2005-11-10
MXPA06011882A (es)	2006-12-14
AU2005238432A1 (en)	2005-11-10
DK1735321T3 (da)	2009-01-12
EP1735321A1 (en)	2006-12-27
US7445916B2 (en)	2008-11-04
JP2007532655A (ja)	2007-11-15
DE602005010228D1 (de)	2008-11-20
EP1735321B1 (en)	2008-10-08
US20090029426A1 (en)	2009-01-29

Publication	Publication Date	Title
ES2313328T3 (es)	2009-03-01	Procedimiento para la preparacion de 42-esteres de rapamicina y 32-esteres de fk-506 con acido dicarboxilico, precursores para conjugados de rapamicina y anticuerpos.
USRE39151E1 (en)	2006-06-27	Process for the preparation and purification of thiol-containing maytansinoids
US7605257B2 (en)	2009-10-20	Processes for preparing water-soluble polyethylene glycol conjugates of macrolide immunosuppressants
KR100342624B1 (ko)	2002-11-18	효소가수분해에의한c-10및c-13히드록실-함유탁산의제조방법,효소에스테르화에의한c-10아실옥시-함유탁산의제조방법,및c-13아실옥시-함유탁산제조에있어서의그들의용도
WO1993025533A1 (en)	1993-12-23	Methods and reagents for the determination of immunosuppressive agents
AU2010250802B2 (en)	2014-05-22	A chemo-enzymatic approach to the synthesis of pimecrolimus
US4920218A (en)	1990-04-24	Novel hydroxide mediated FK-506 rearrangement process
EP0364031B1 (en)	1992-12-23	Hydroxide mediated fk-506 rearrangement process
EP0364032A3 (en)	1991-03-13	Novel hydroxide mediated fk-506 rearrangement product
Niwa et al.	1994	A Synthesis of Senecionine, a Representative of Hepatotoxic, Macrocyclic Pyrrolizidine Alkaloids of Retronecine Type.
WO2003057896A1 (en)	2003-07-17	Methods for preparing anthracyclinone derivatives and anthracyclinone derivatives per se
US4980466A (en)	1990-12-25	Hydroxide mediated FK-506 rearrangement product
HK1164886B (en)	2015-12-04	A chemo-enzymatic approach to the synthesis of pimecrolimus
EP0307223A2 (en)	1989-03-15	Process for the preparation of macrolide compounds
JPH06206897A (ja)	1994-07-26	新規１６員環マクロリド誘導体